Genetic Variant CCDC18:p.Ile1306Phe (chr1-93270377-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378204.1(CCDC18):c.3916A>T(p.Ile1306Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,549,016 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 32)

Exomes 𝑓: 0.025 ( 510 hom. )

Consequence

CCDC18
NM_001378204.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

CCDC18 (HGNC:30370): (coiled-coil domain containing 18)

CCDC18 links:

CCDC18-AS1 (HGNC:52262): (CCDC18 antisense RNA 1)

CCDC18-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023387074).

BP6

Variant 1-93270377-A-T is Benign according to our data. Variant chr1-93270377-A-T is described in ClinVar as [Benign]. Clinvar id is 3038261.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0209 (3176/152294) while in subpopulation NFE AF= 0.027 (1837/68008). AF 95% confidence interval is 0.026. There are 50 homozygotes in gnomad4. There are 1650 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC18	NM_001378204.1 link	c.3916A>T	p.Ile1306Phe	missense_variant	Exon 28 of 29	ENST00000690025.1	NP_001365133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC18	ENST00000690025.1 link	c.3916A>T	p.Ile1306Phe	missense_variant	Exon 28 of 29		NM_001378204.1	ENSP00000510597.1		A0A8I5KWA2

Frequencies

GnomAD3 genomes

AF:

0.0209

AC:

3179

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0562

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0235

GnomAD3 exomes

AF:

0.0241

AC:

3574

AN:

148572

Hom.:

AF XY:

0.0242

AC XY:

1940

AN XY:

80036

show subpopulations

Gnomad AFR exome

AF:

0.00385

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0000928

Gnomad SAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0270

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0255

AC:

35547

AN:

1396722

Hom.:

510

Cov.:

AF XY:

0.0252

AC XY:

17335

AN XY:

688758

show subpopulations

Gnomad4 AFR exome

AF:

0.00406

Gnomad4 AMR exome

AF:

0.0154

Gnomad4 ASJ exome

AF:

0.0177

Gnomad4 EAS exome

AF:

0.0000841

Gnomad4 SAS exome

AF:

0.0230

Gnomad4 FIN exome

AF:

0.0549

Gnomad4 NFE exome

AF:

0.0264

Gnomad4 OTH exome

AF:

0.0229

GnomAD4 genome

AF:

0.0209

AC:

3176

AN:

152294

Hom.:

Cov.:

AF XY:

0.0222

AC XY:

1650

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00438

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0205

Gnomad4 FIN

AF:

0.0562

Gnomad4 NFE

AF:

0.0270

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0230

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0228

AC:

ExAC

AF:

0.0232

AC:

434

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CCDC18-related disorder

Benign:1

Jun 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

PROVEAN

Benign

-2.0

REVEL

Benign

0.073

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.018

Vest4

0.14

ClinPred

0.033

GERP RS

3.7

Varity_R

0.22

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over